Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 292, Issue 2, Pages E421-E434Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00157.2006
Keywords
hypertriglyceridemia; forkhead box O1; peroxisome proliferator-activated receptor-alpha; apolipoprotein C-III; very-low-density lipoprotein-triglyceride; microsomal triglyceride transfer protein
Categories
Funding
- NIDDK NIH HHS [DK-066301, R01 DK066301-01A3, R01 DK066301] Funding Source: Medline
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High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that high-fructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-gamma coactivator-1 beta and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-alpha (PPAR alpha). PPAR alpha physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPAR alpha constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.
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